Filgrastim (recombinant metHu G-CSF) is indicated in clinical conditions where it is desired to have increased production of circulating neutrophils. Common clinical indications include, severe chronic neutropenia, bone marrow transplants, and patients undergoing chemotherapy for various cancers. One of the drawbacks of the current filgrastim therapy protocol is the need for daily or twice-daily injections. This comes as a result of the short half-life of the drug of only several hours (1).
Recently several drugs have been developed that have sought to address the short half-life of filgrastim. For example, these have included pegylation of G-CSF (2) and the creation of G-CSF-albumin fusion constructs (3). Reduced clearance rates of the protein-drug have been reported for these modifications to G-CSF. However, these alterations to standard filgrastim dosing regimes are still limited to invasive administration.
The current subcutaneous filgrastim dosing regime is less than ideal for the patient because of the inconvenience and pain brought about by repeated injections. Non-invasive delivery methods have been a subject of interest for protein-based therapeutics as an alternative to the current subcutaneous or IV dosing. Nasal (4), rectal (5), pulmonary (6):361-373), ocular (7), and oral administration routes are among those that have been investigated. Among all of these, oral is the most preferred because it requires no specialized delivery device and it is most convenient for the patient. However, oral delivery of protein-drugs is hampered by negligible bioavailability. Protein based drugs are hampered by instability and proteolysis in the gastro-intestinal tract. The large size and charged nature of the molecules also prevents them from traversing biological barriers. Co-administration and/or formulation with penetration enhancers and enzymatic inhibitors has been suggested as a means to achieve oral bioavailability of protein-drugs (8; 9). However, the suitability of these methods for chronic usage remains questionable as they have been shown to be associated with adverse side-effects (10-12). Development of new dosing regimes is needed.